Inflammatory bowel disease (IBD) is the name given to a group of diseases causing chronic inflammation of the gastrointestinal tract. It is an idiopathic disease caused by a dysregulated immune response to host intestinal microflora. The course of IBD varies widely, with intermittent periods of remission followed by periods of acute illness. The 2 major types of IBD are ulcerative colitis and Crohn's disease.
Ulcerative colitis affects the colon and rectum and typically involves only the innermost lining or mucosa, manifesting as continuous areas of inflammation and ulceration, with no segments of normal tissue. The disease involving only the most distal part of the colon and the rectum, termed as ulcerative proctitis; disease from the descending colon down is referred to as limited or distal colitis; whereas disease involving the entire colon is called pancolitis (Kathleen Head et al; Altern Med Rev. 2003; 8(3):247-83).
Crohn's disease is transmural (affecting all layers of the intestine) inflammation that can affect any portion of the digestive tract from mouth to anus, but is predominantly seen in the terminal ileum and/or colon. Intestinal inflammation and ulceration in Crohn's disease is asymmetrical and occurs in “patches,” with areas of healthy tissue interspersed, and extends deeply into the intestinal wall, forming granulomatous lesions. Several categories of Crohn's disease have been described, defined by the portion of the digestive tract involved and the presenting symptomatology (Kathleen Head et al; Altern Med Rev. 2004; 9(4):360-401). The symptoms are often more variable than ulcerative colitis depending on which part of the bowel is involved.
Clinical symptoms of IBD include abdominal cramps and pain, bloody diarrhea, severe urgency to have a bowel movement, sensation of incomplete evacuation, fever, loss of appetite, weight loss and anemia. Available therapeutic strategies for management of IBD include 5-aminosalicylate (mesalamine), corticosteroids, immunomodulators, antibiotics and anti-tumor necrosis factor (TNF) agents. Most commonly used medication for IBD is mesalamine, which is available in the dose strengths range 250 mg to 2 g, which are recommended for dose of at least 1 g per day or even higher by oral route of administration. Though mentioned therapeutic strategies are found useful, non-responsiveness of patients to 5-aminosalicylate, side-effects associated with high-level and prolonged corticosteroid usage and non-response/loss of response, high cost and increased risk of infection and malignancy with the use of biologic agents, especially when combined with immunomodulators are limiting (Cummins et al; Lab Invest. 2013; 93: 378-383). This indicates at existence of gap in the available therapeutics and re-inforces need for the development of newer therapeutic approaches for the treatment of IBD. Also, as mentioned, IBD is a chronic disease, the medication is required for longer duration of time, for example, mesalamine is recommended generally for 6 to 8 weeks for the total daily dose of 4 g by oral route. Therefore, high dose medication for longer duration may reduce patient compliance.
Although exact etiology for IBD is not yet established but it has been found by researchers that during IBD, increased tissue metabolism and vasculitis renders the chronically inflamed mucosa and particularly the epithelium hypoxic, giving rise to the activation of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF).
The protective role of HIF-1 in murine colitis was first investigated by Karhausen et al (J Clin Invest. 2004; 114: 1098-1106). Conditional deletion of HIF-1α in colonic epithelium increased the severity of colitis and barrier dysfunction in both the oxazolone- and trinitrobenzene sulfonic acid (TNBS)-induced model of acute colitis. HIF activation is also known for up-regulation of set of target genes linked with maintenance of intestinal barrier function such as HSP 70 and anti-inflammatory cytokines interleukin (IL)-10 (Braat et al; Clinical Gastroenterology and Hepatology 2006; 4:754-759)
Intestinal epithelial HSP70 plays an important role in protecting mucosal integrity and function by stabilizing the tight junctions between intestinal epithelial cells. Such intestinal epithelial protection is associated with restricted bacterial translocation and a reduction in inflammation (Liedel J L et al; Pediatr Res. 2011; 69:395-400). Also IL-10 expression is directly linked with inflammatory disorders. It was shown that IL-10-deficient mice develop a chronic bowel disease resembling Crohn's disease in human beings and intragastric administration of recombinant lactococcus lactis strain secreting murine IL-10, prevented onset of colitis in IL-10 knockout mice, and caused a 50% reduction of the inflammation in dextran sulfate sodium-induced chronic colitis. (Braat et al; Clinical Gastroenterology and Hepatology 2006; 4:754-759)
WO2009002533 discloses method for treating IBD by administering an agent that inhibits HIF hydroxylase activity. It discloses pyridine-2-carboxamide, quinoline-2-carboxamide and isoquinoline-3-carboxamide as HIF hydroxylase inhibitors for treatment of IBD. It discloses that compound was administered daily as intraperitoneal dose in TNBS induced animal model of colitis at the dose of 20 mg/kg and 40 mg/kg, and higher dose was found more effective.
Above data shows that disclosed HIF hydroxylase inhibitors may have potential in treatment of IBD in animals. However there is no conclusive evidence available yet that HIF hydroxylase inhibitor can be effective for the treatment of IBD, particularly by oral administration and there is no HIF hydroxylase inhibitor drug yet available in the market which could be used for treatment of IBD effectively.
WO2011045811 discloses oxazolo and thiazolo derivatives as HIF hydroxylase inhibitors for treatment of anemia, ischemia or tissue damage caused by ischemic disorders. It discloses that compound 10 was effective for chronic kidney disorder (CKD) at higher doses such as at the dose of 20 mg/kg bid (approx 450 mg/day equivalent human dose), when administered through intraperitoneal route to diseased animals.
Jamadarkhana et al discloses in Am J. of nephrology (2012, 36: 208-218) that compound [(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, a novel HIF hydroxylase inhibitor, when administered intraperitoneally it was found effective in prevention and for treatment of ischemic acute kidney injury (AKI).
Both Jamadarkhana et al and WO2011045811 teach to use HIF hydroxylase inhibitor, [(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid, for the treatment of anemia, ischemia or tissue damage caused by ischemic disorder such as CKD or AKI, specifically by parenteral route.
Present invention provides a low dose pharmaceutical composition for non-parenteral administration, preferably for oral administration, comprising HIF hydroxylase inhibitor, [(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diaza-benzo[a]azulene-3-carbonyl)-amino]-acetic acid (hereinafter mentioned as compound A) which is useful in the dosage range of 2.5 mg to 60 mg per day for treating inflammatory bowel disease (herein after referred as IBD). Present invention also provides a method of treating inflammatory bowel disease in a mammal by administering low dose pharmaceutical compositions comprising therapeutically effective amount of compound A, which is effective in low dosage range of 2.5 mg to 60 mg per day.